Autism spectrum disorder (ASD) is characterized by marked impairments in social and non-social cognitive ability that persist well into adulthood and contribute to significant functional disability. The treatment of ASD has focused almost exclusively on children, and few empirically supported interventions are available to address the core cognitive and functional challenges individuals with ASD face as they transition to adulthood. Cognitive rehabilitation has emerged as a set of systematic approaches to the remediation of cognitive impairments that hold considerable promise for the treatment of cognitive deficits in autism, yet adequately-powered and rigorously controlled studies of these interventions have not been conducted in this population. Cognitive Enhancement Therapy (CET) represents one of the most promising cognitive rehabilitation approaches for adult ASD due to its comprehensive and developmental approach to targeting neurocognitive and social-cognitive impairments as well as its established efficacy in schizophrenia, a disorder characterized by similar cognitive deficits. With support from NIMH, we have recently demonstrated the feasibility of adapting CET to adults with ASD, and evidence is emerging from our initial, small-scale randomized trial of CET in this population indicating target engagement on diverse areas of cognition with substantial downstream benefits to functional outcomes. Excitingly, these improvements in cognition associated with CET also appear to be supported by underlying neuroplastic changes in fronto-temporal brain function and connectivity. Such evidence suggests that CET has considerable promise as an evidence-based cognitive rehabilitation intervention for adult ASD, and it is critical that these early findings are followe-up with an adequately-powered efficacy trial. In response to the psychosocial intervention focus of PA-13-216, Research on Autism Spectrum Disorders, this project proposes to conduct a randomized-controlled efficacy trial of CET in 100 verbal adults with ASD. Participants will be randomized to CET or an Enriched Supportive Therapy (EST) control condition and treated for 18 months. Specific aims of the project are to (1) evaluate the comparative effectiveness of CET versus EST on diverse cognitive and behavioral outcomes to assess target engagement and functional impact, (2) examine the effects of CET on fronto-medial temporal brain function and connectivity to elucidate the neural mechanisms of cognitive enhancement in this population, and (3) use personal and neurobiological indicators to explore heterogeneity in treatment response and identify moderators indicative of individuals most likely to benefit from CET. The proposed project will result in the largest psychosocial intervention study in adult ASD, and the first adequately-powered study of a promising cognitive rehabilitation approach for this population. If successful, this project will provide a major step forward in making interventions available for adults with ASD, and will demonstrate the plasticity of the adult ASD brain and its responsiveness to cognitive rehabilitation, paving the way for a new generation of treatments in autism.